Abstract

Anti-diabetic treatments aiming to preserve or even to increase beta cell mass are currently gaining increased interest. Here we investigated the effect of chronic treatment with the novel glucagon-like peptide-1 (GLP-1)-gastrin dual agonist, ZP3022, on glycemic control, beta cell mass and proliferation, and islet number. Male db/db mice were treated with ZP3022, liraglutide, or vehicle for 2, 4, or 8 weeks with terminal assessment of HbA1c, basal blood glucose, and plasma insulin concentrations. Pancreata were removed for immunohistochemical staining and stereological quantification of beta cell mass, islet numbers, proliferation, and apoptosis. Treatment with ZP3022 or liraglutide led to a significant improvement in glycemic control. ZP3022 treatment resulted in a sustained increase in beta cell mass after 4 and 8 weeks treatment, whereas the effect of liraglutide was transient. The expansion in beta cell mass observed in the ZP3022 treated mice appeared to be driven by an increased beta cell proliferation in existing islets rather than by formation of new islets, as mean islet mass increased, but the number of islets remained constant. Our data demonstrates that the GLP-1-gastrin dual agonist, ZP3022, causes a sustained improvement in glycemic control accompanied by an increase in beta cell mass, increased proliferation, and increased mean islet mass. The results highlight that the GLP-1-gastrin dual agonist increases beta cell mass more than liraglutide and that dual agonists could potentially be developed into a new class of anti-diabetic treatments.